Effects of MCC950 on nerve injury in rats with intracerebral hemorrhage / 中国应用生理学杂志

Objective: To investigate the effects of the pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950 on nerve injury in rats with intracerebral hemorrhage(ICH). Methods: Seventy-two SD rats were randomly divided into three groups (n=24): Sham group, ICH group and MCC950 group. ICH group and MCC950 group rats were injected with autogenous non-anticoagulant blood to establish ICH model, and then the rats in MCC950 group were intraperitoneally injected with MCC950 at the dose of 10 mg/kg(2 mg/ml) for 3 days after ICH model was established. Seventy-two hours after the establishment of the model, the forelimb placement test, the corner test and mNSS score were performed to observe the neurological function of the rats with ICH. The volume of hematoma was observed in fresh brain tissue sections. HE staining was used to observe the pathological changes of brain tissue. The dry-wet weight ratio was calculated to evaluate the changes of brain tissue edema. The degeneration of neurons was observed by FJC staining. The neuronal apoptosis was observed by TUNEL staining. The protein expression and activation levels of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD were determined by Western blot. Results: Compared with sham group, the percentage of successful placement of left forelimb and left turn was decreased significantly (P＜0.01, P＜0.05), mNSS score was increased significantly (P＜0.01) in ICH group. Hematoma volume was increased significantly, the number of microglial cells around the hematoma was increased, the number of neurons was decreased, nerve cell swelled, some cells showed pyknotic necrosis, and the staining was deepened. The water content of the right base was increased significantly (P＜0.05). The number of FJC positive and TUNEL positive cells around the hematoma was increased significantly (P＜0.05). The levels of NLRP3, ASC, caspase-1, pro-caspase-1, caspase-1/pro-caspase-1 ratio, GSDMD-N, GSDMD, GSDMD-N/GSDMD ratio, IL-1β and IL-18 were increased significantly (P＜0.01, P＜ 0.05). Compared with ICH group, the percentage of successful placement of left forelimb and left turn was increased significantly in MCC950 group (P＜0.05), while the mNSS score and the volume of hematoma were decreased significantly (P＜0.01), the swelling degree of nerve cells around the hematoma was reduced significantly, and the number of pyrotic necrotic cells was decreased. The water content of the right base was decreased significantly (P＜0.05), and the number of FJC positive and TUNEL positive cells around the hematoma was decreased significantly (P＜0.05). The levels of NLRP3, ASC, caspase-1, pro-caspase-1, caspase-1/pro-caspase-1 ratio, GSDMD-N, GSDMD, GSDMD-N/GSDMD ratio, IL-1β and IL-18 were decreased significantly (P＜0.05). Conclusion: MCC950 can ameliorate nerve injury after ICH by inhibiting NLRP3 inflammasome mediated inflammation and pyroptosis.

Reproductive toxicity of brazilein in ICR mice / 中国天然药物

Brazilein is an active small molecular compound extracted from Caesalpinia sappan L. with favorable pharmacological properties on immune system, cardiovascular system, and nervous system. C. sappan has been used as a traditional medicine in China for hundreds of years for various diseases. However, the general reproductive toxicity of brazilein is still unknown. The purpose of the present study was to thoroughly evaluate the general reproductive toxicity of brazilein in ICR mice to support the future drug development and modernization of this potent traditional Chinese medicine. The results showed that, although no apparent toxicity on the reproducibility of the male was observed, brazilein might cause considerable risks to the fetuses and females as indicated by the ratios of dead fetuses and reabsorptions. In conclusion, our results from the present study provided some useful insights about the safety profile of brazilein, suggesting that brazilein should be used with caution in pregnant women.

Brazilein inhibits neuronal inflammation induced by cerebral ischemia and oxygen-glucose deprivation through targeting NOD2 expression / 中国天然药物

Brazilein is reported to have immunosuppressive effect on cardiovascular and cerebral-vascular diseases. The essential roles of innate immunity in cerebral ischemia are increasingly identified, but no studies concerning the influence of brazilein on the innate immunity receptors have been reported. The present study was designed to investigate the regulation of NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) by brazilein for its protection of neuron in cerebral ischemia in vivo and oxygen-glucose deprivation in vitro. The results showed that brazilein could reverse the elevated expression of NOD2 and TNFα (tumor necrosis factor alpha) elicited by cerebral ischemia and reperfusion. This reduction could also be detected in normal mice and C17.2 cells, indicating that this suppressive effect of brazilein was correlated with NOD2. The results from GFP reporter plasmid assay suggested brazilein inhibited NOD2 gene transcription. In conclusion, brazilein could attenuate NOD2 and TNFα expression in cerebral ischemia and NOD2 may be one possible target of brazilein for its immune suppressive effect in neuro-inflammation.

Inhibition of Ubiquitin-specific Peptidase 8 Suppresses Adrenocorticotropic Hormone Production and Tumorous Corticotroph Cell Growth in AtT20 Cells / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Two recent whole-exome sequencing researches identifying somatic mutations in the ubiquitin-specific protease 8 (USP8) gene in pituitary corticotroph adenomas provide exciting advances in this field. These mutations drive increased epidermal growth factor receptor (EGFR) signaling and promote adrenocorticotropic hormone (ACTH) production. This study was to investigate whether the inhibition of USP8 activity could be a strategy for the treatment of Cushing's disease (CD).</p><p><b>METHODS</b>The anticancer effect of USP8 inhibitor was determined by testing cell viability, colony formation, apoptosis, and ACTH secretion. The immunoblotting and quantitative reverse transcription polymerase chain reaction were conducted to explore the signaling pathway by USP8 inhibition.</p><p><b>RESULTS</b>Inhibition of USP8-induced degradation of receptor tyrosine kinases including EGFR, EGFR-2 (ERBB2), and Met leading to a suppression of AtT20 cell growth and ACTH secretion. Moreover, treatment with USP8 inhibitor markedly induced AtT20 cells apoptosis.</p><p><b>CONCLUSIONS</b>Inhibition of USP8 activity could be an effective strategy for CD. It might provide a novel pharmacological approach for the treatment of CD.</p>

Effects of Kaixin Powder on melatonin receptor expression and (125)I-Mel binding affinity in a rat model of depression / 中国结合医学杂志

<p><b>OBJECTIVE</b>To explore the effects of Kaixin Powder (, KXP) on melatonin receptor (MR) expression and (125)I-Mel binding affinity in a depression rat model.</p><p><b>METHODS</b>Seventy-two male Wistar rats were divided into six groups: a blank control group, model group, ramelteon group, KXP high-dosage group (HKXP), medium-dosage group (MKXP) and low-dosage group (LKXP). To establish the depression model, all groups except the blank control group were singly housed and exposed to chronic unpredictable mild stress. Weight gain, sucrose consumption and the open-field test were used to evaluate induction of depression. KXP at 260, 130 and 65 mg/(kg•d) was also respectively administered to the rats in the HKXP, MKXP and LKXP groups for 21 days. Ramelteon [0.83 mg/(kg•d)] was given to the positive drug control group. An equivalent volume of physiological saline was given to the blank and model groups. The liquid chip method was used to measure the concentration of plasma melatonin (MT). Mel1a (MT1) and Mel1b (MT2) expression levels were determined by Western blotting. In addition, a radioactive ligand-binding assay was used to analyze the specific binding properties and dynamic characteristics between MR and (125)I-Mel.</p><p><b>RESULTS</b>The results of weight gain, sucrose consumption and the open-field test showed that our model successfully produced depressive symptoms and depressive-like behavior. The concentration of plasma MT in the model group decreased significantly at night but increased in the MKXP group (P<0.05). The HKXP group showed significantly increased expression of MT1 (P<0.05); however, the expression of MT2 in all groups exhibited no significant differences (P>0.05). The maximum binding capacity (B(max)) for specific binding between MR and 125I-Mel in the MKXP group was significantly higher than that in the model group (P<0.05), but no significant differences were found in the equilibrium dissociation constant (K(d)) of each group (P>0.05).</p><p><b>CONCLUSIONS</b>KXP may have a similar effect as ramelteon. KXP improved depressive-like behavior by increasing the concentration of plasma MT and MT1 expression, thereby increasing three B(max) of MR to achieve the desired antidepressant effect.</p>

Muscular performance characterization in athletes: a new perspective on isokinetic variables

Background: Isokinetic dynamometry allows the measurement of several variables related to muscular performance, many of which are seldom used, while others are redundantly applied to the characterization of muscle function. Objectives: The present study aimed to establish the particular features of muscle function that are captured by the variables currently included in isokinetic assessment and to determine which variables best represent these features in order to achieve a more objective interpretation of muscular performance. Method: This study included 235 male athletes. They performed isokinetic tests of concentric knee flexion and extension of the dominant leg at a velocity of 60º/s. An exploratory factor analysis was performed. Results: The findings demonstrated that isokinetic variables can characterize more than muscle torque production and pointed to the presence of 5 factors that enabled the characterization of muscular performance according to 5 different domains or constructs. Conclusions: The constructs can be described by torque generation capacity; variation of the torque generation capacity along repetitions; movement deceleration capacity; mechanical/physiological factors of torque generation; and acceleration capacity (torque development). Fewer than eight out of sixteen variables are enough to characterize these five constructs. Our results suggest that these variables and these 5 domains may lead to a more systematic and optimized interpretation of isokinetic assessments. .

Idosos residentes em uma instituição de longa permanência: adaptação à luz de Callista Roy / Elderly residents in homes for the aged: adjustment in the light of Callista Roy / Residentes mayores en un hogares para ancianos: adaptación a la luz de Callista Roy

Objetivou-se avaliar o processo de adaptação de idosos que buscam, voluntariamente, residir em Instituição de Longa Permanência para Idosos (ILPI), na cidade de Fortaleza-CE, com base no modelo teórico de Roy. Pesquisa descritiva, realizada em uma IPLI com treze idosos residentes. A coleta de dados foi por meio de entrevista, nos meses de outubro e dezembro de 2011. Os dados foram tratados pela análise de conteúdo temática. Emergiram as seguintes temáticas: Eu Físico, subdividido em sensação corporal e imagem corporal; e Eu Pessoal, subdividido em auto coerência, auto ideal e ser moral-ético-espiritual. Assim, a opção de morar em ILPI não mudou efetivamente a vida dos idosos. Estes conseguiram adaptação ao local e convivem bem com os estímulos internos e externos.

This study aimed to evaluate the adaptation of elderly individuals voluntarily reside in Institution for the Aged (LTCF) in the city of Fortaleza-CE, based on the theoretical model of Roy. Descriptive study, in a IPLI involving thirteen elderly residents. Data collect was through interviews in the months of October and December 2011 and organized by thematic content analysis. The following themes has emerged: I Physical subdivided into body sensation and body image; Staff and I, subdivided into self-consistency and auto ideal be moral-ethical-spiritual. Thus, the option to live in ILPI not effectively changed the lives of elderly people. They managed to adapt to the local and coexist well with internal and external stimuli.

Este estudio tuvo como objetivo evaluar la adaptación de las personas mayores que residen voluntariamente en la Institución para la tercera edad (LTCF) en la ciudad de Fortaleza-CE, basado en el modelo teórico de Roy. Estudio descriptivo, en un IPLI con trece ancianos residentes. Los datos fueran recogidos a través de entrevistas en los meses de octubre y diciembre de 2011 y organizados mediante análisis de contenido temático. Emergieron los siguientes temas: subdivide I Física en la imagen corporal y sensación de cuerpo; El personal y yo, subdividen en auto-consistencia y auto ideal ser moral-ético-espiritual. Por lo tanto, la opción de vivir en ILPI no cambió de manera efectiva la vida de los ancianos. Se las arreglaron para adaptarse a lo local y convivir bien con los estímulos internos y externos.

Optimization of zofimarin production by an endophytic fungus, Xylaria sp. Acra L38

To optimize the medium for high zofimarin production, sucrose maltose, glucose, tryptone and peptone were used in an orthogonal array design experiment, where the highest value of zofimarin produced was 25.6 µg/mL. This value was about 3 times higher than that obtained with Czapek yeast extract (CzYE) culture medium. A study with Plackett-Burman design showed that sucrose, maltose, glucose and NaNO3 were significant factors in zofimarin production. Further studies using central composite design (CCD) showed the significance of glucose and the interactions of these critical components affecting zofimarin production. Multiple regression analysis of the data yielded a poor fit as shown by the mismatch of the model with these variable factors. When a polynomial equation was applied, the maximum zofimarin production was predicted to be 201.9 µg/mL. Experimental verification yielded a much lower amount of zofimarin, at around 70 µg/mL. Reconsideration of the CCD data and repetition of some runs with high zofimarin production resulted in reproducible zofimarin yield at 79.7 µ/mL. Even though the amount was lower than the predicted value, the medium optimization study was considered to be quite successful as the yield increased to around 8 times that obtained with the original CzYE culture medium.

Design, synthesis, and PPARgamma agonistic activity of novel indenone derivatives / 药学学报

Agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) are of interest as a treatment of type II diabetes, and indenone derivatives are a new class of non-TZD PPARgamma agonists. Based on existing indenone derivatives, a series of novel ones have been designed and synthesized. Meanwhile the structures have been comfirmed with 1H NMR and MS. Among them, 17b and 19 showed higher agonistic activities than rosiglitazone.

Sesquiterpenoids of Coniogramme maxima / 中国中药杂志

<p><b>OBJECTIVE</b>To study sesquiterpenoids of Coniogramme maxima.</p><p><b>METHOD</b>Chemical constituents were separated by chromatography and their structures were identified according to physicochemical property and spectrum data.</p><p><b>RESULT</b>Fifteen compounds were separated by chromatography technique. Their structures were determined by spectral data, including 10 sesquiterpenoids as (3S)-pteroside D (1), epi-pterosin L (2), pterosin D (3), onitin (4), pterosin Z (5), onitisin (6), onitisin-glucopyranoside (7), onitin-15-O-beta-D-glucopyranoside (8), (2S,3R)-pterosin-L-2'-O-beta-D-glucopyranoside (9) and (3R)-peterosin D-3-O-beta-D-glucopyranoside (10). The other compounds were uracil (11), 3,4-dihydroxybenzaldehyde (12), 5-hydroxymethyl-2-furancarboxaldehyde (13), beta-sitosterol (14) and daucosterol (15).</p><p><b>CONCLUSION</b>The above 15 compounds are separated from C. maxima for the first time, including 9 compounds being first separated from genus Coniogramme.</p>

Effects of Chronic Mild Stress in Female Bax Inhibitor-1-Gene Knockout Mice

OBJECTIVE: The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress, and BI-1-/- mice exhibit increased sensitivity to tissue damage. The purpose of this study was to investigate the role of BI-1 in the pathogenesis of chronic mild stress (CMS)-induced depression-like behaviors in BI-1-/- mice. METHODS: We delivered CMS for 2 or 6 weeks in BI-1-knockout and wild-type mice. Control groups of BI-1-knockout and wild-type mice were left undisturbed. The measured parameters were sucrose consumption at weeks 1, 2, 3, 4, 5, and 6, spontaneous locomotion, and a forced swimming test (FST) at weeks 2 and 6. RESULTS: Significant decreases in sucrose consumption and increases in immobility time in the FST were observed in both stress groups compared with the non-stress groups. Interestingly, at week 2, but not at week 6, BI-1-/--stress mice showed less sucrose intake and greater immobility time than did BI-1+/+-stress mice. CONCLUSION: These results suggest that BI-1 may play role in protecting against the depressogenic effects of CMS in the short term, but not in the long term. Further study is required to deepen understanding of the role of BI-1 in protecting against depression.

Antiparasitic activity of plumericin & isoplumericin isolated from Plumeria bicolor against Leishmania donovani.

Background & objectives: The severe toxicity, exorbitant cost and emerging resistance of Leishmania species against most of the currently used drugs underscores the urgent need for the alternative drugs. The present study evaluates in vitro anti-leishmanial activity of Plumeria bicolor and its isolated compounds. Methods: The in vitro anti-parasitic activity of chloroform extract of Plumeria bicolor, plumericin and isoplumericin were tested alongwith appropriate controls against promastigote and amastigote forms of Leishmania donovani using 96 well microtiter plate. The concentration used for assessing the anti-leishmanial activity of extract of Plumeria bicolor and both isolated compounds were 100 μg/ml and 15 μM, respectively. The viability of the cells was assessed by MTT assay. The cytotoxicity of these compounds was performed against J774G8 murine macrophage cells lines at the concentration of 30 μM. Results: The Plumeria bicolor extract showed activity with the IC50 of 21±2.2 and 14±1.6 μg/ml against promastigote and amastigote forms of L. donovani, respectively. Plumericin consistently showed high activity with the IC50 of 3.17±0.12 and 1.41±0.03 μM whereas isoplumericin showed the IC50 of 7.2±0.08 μM and 4.1±0.02 μM against promastigote and amastigote forms, respectively. Cytotoxic effect of the chloroform extract of P. bicolor, plumericin and isoplumericin was evaluated in murine macrophage (J774G8) model with CC50 value of 75±5.3 μg/ml, 20.6±0.5 and 24±0.7 μM, respectively. Interpretation & conclusions: Our results indicated that plumericin showed more potent activity than isoplumericin and might be a promising anti-leishmanial agent against L. donovani.

Molecular battles between plant and pathogenic bacteria in the phyllosphere

The phyllosphere, i.e., the aerial parts of the plant, provides one of the most important niches for microbial colonization. This niche supports the survival and, often, proliferation of microbes such as fungi and bacteria with diverse lifestyles including epiphytes, saprophytes, and pathogens. Although most microbes may complete the life cycle on the leaf surface, pathogens must enter the leaf and multiply aggressively in the leaf interior. Natural surface openings, such as stomata, are important entry sites for bacteria. Stomata are known for their vital role in water transpiration and gas exchange between the plant and the environment that is essential for plant growth. Recent studies have shown that stomata can also play an active role in limiting bacterial invasion of both human and plant pathogenic bacteria as part of the plant innate immune system. As counter-defense, plant pathogens such as Pseudomonas syringae pv tomato (Pst) DC3000 use the virulence factor coronatine to suppress stomate-based defense. A novel and crucial early battleground in host-pathogen interaction in the phyllosphere has been discovered with broad implications in the study of bacterial pathogenesis, host immunity, and molecular ecology of bacterial diseases.

Effect of brazilein on energy metabolism of cerebral ischemia-reperfusion in mice / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate brazilein's role in energy metabolism of cerebral ischemia-reperfusion in mice.</p><p><b>METHOD</b>Fourty mice were randomly divided into the sham group, ischemia group, brazilein 5 mg x kg(-1) group and brazilein 10 mg x kg(-1) group, each with ten cases. Cerebral ischemia model was the built. Mice were injected with brazilein three days before the operation, then they were killed. Cerebrum homogenate was prepared for the detecting of ATP, ADP, AMP and lactic acid by HPLC, expressions of MCT1 and MCT2 in mRNA level by RT-PCR.</p><p><b>RESULT</b>The lactic acid in cerebrum increased sharply 20 minutes after cerebral ischemia and decreased 1 hour after reperfusion, then returned to the normal level 24 hours after reperfusion. The charge of energy decreased significantly at the beginning of the ischemia-reperfusion, and the charge restored 1 hour after reperfusion though it was still much lower than the normal level at the time point of 24 hours. Moreover, MCT1 and MCT2 upregulated accompanied with the increase of lactate, MCT2 mRNA enhanced in brazilein 5 mg x kg(-1) group (P < 0.05) while both the two factors increased in brazilein 10 mg x kg(-1) group (P < 0.01).</p><p><b>CONCLUSION</b>Brazilein might protect neurons by changing the charge of energy.</p>

Ramelteon: a melatonin receptor agonist for the treatment of insomnia.

Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use > 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon's properties.

Interaction between (E)-2-(4-(diethylamino methyl) benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one and P-glycoprotein / 药学学报

Cell lines of Bcap37 and Bcap37/MDR1 (the high P-glycoprotein (P-gp) expressing cell line) were used as model to investigate the different accumulations of (E)-2-(4-(diethylamino methyl) benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one (BYZX) in the two kinds of cells. It was authenticated that whether BYZX was the substrate of P-gp. Meanwhile, the inhibitive effects of BYZX on the P-gp were investigated by determining the fluorescence intensity of rhodamine 123 in the model cells, with and without BYZX. A reversed-phase high-performance liquid chromatography (RP-HPLC) method was used to determine the accumulations of BYZX in the two cells. The results showed that the amount of BYZX accumulation in Bcap37/MDR1 cells were as many as those in Bcap37 cells (P > 0.05), and the concentrations of BYZX accumulated in the Bcap37/MDR1 cells did not increase when co-incubated with P-gp inhibitor verapamil. Furthermore, different concentrations of BYZX also had no effects on the efflux of rhodamine 123 (P > 0.05). These results indicated that there were no interactions between BYZX and P-gp. BYZX will not be pumped out of the cells, and it also not inhibited the P-gp. It was the useful advantage for its absorption.

Formulation and pharmaceutical evaluation of sulindac suspensions

Sulindac has been introduced in suspension dosage form which has suited its low aqueous solubility, its use in the fields of pediatrics and geriatrics, and its requirement of dose flexibility. A wettability study showed that 0.05% tween 20 was the wetting agent of choice. Controlled flocculation was adopted to prepare the flocculated suspensions. 32 deflocculated as well as 20 flocculated suspension formulations were prepared using different classes of suspending agents. The parameters used for evaluation were the sedimentation volume ratio [Vu/Vo], easiness of sediment redispersibility, clarity and color of supernatant, the time of the suspension has remained dispersed after being shaken, degree of flocculation, pH stability, conductivity, specific gravity, rheological properties, and dissolution. The deflocculated formula of choice was formula 18 containing 0.5% xanthan gum. The best flocculated suspension was formula 19 containing 10% glycerin, 10% propylene glycol, and 40% sorbitol as density modifiers

Further evaluation of certain sulindac suspensions

Microscopical characteristics and crystal growth, chemical stability, accelerated stability and the effect of dilution on physical and chemical stability were studied. Stable suspensions of choice were pharmacologically evaluated regarding anti-inflammatory, analgesic, and antipyretic effects as well as ulcerogenesis using laboratory animals. Clinoril tablet, the only marketed sulindac product, was taken as standard for comparison. The deflocculated formula 3 [containing 0.5% w/v xanthan gum] and the flocculated formula c [containing 10% glycerin, 10% propylene glycol, and 40% sorbitol as density modifiers] were the most stable among the tested formulae. The pharmacological evaluation of both suspension formulae showed anti-inflammatory, analgesic and antipyretic effects comparable to those of clinoril tablets; while ulcerogenesis was less. The flocculated suspension was the least ulcerogenic. Moreover, it showed earlier anti-inflammatory, analgesic, and antipyretic responses reflecting faster absorption